Neisseria meningitidis, a common commensal inhabitant of the human nasopharynx, is a major cause of bacterial meningitis and septicaemia worldwide. Acapsulate meningococci are essentially avirulent and only five of the thirteen chemically and immunologically distinct meningococcal capsular polysaccharides, which define meningococcal serogroup, are frequently associated with invasive disease. Although protein-polysaccharide conjugate vaccines offer the possibility of protection against meningococcal disease caused by serogroups A, C, Y and W135, this approach has not been successful for serogroup B meningococci. Furthermore, comprehensive prevention does not appear possible with polysaccharide-based vaccines alone. Problems arise from the fact that the serogroup B polysaccharide structure is poorly immunogenic. Further problems arise due to its similarity to sialylated glycopeptides on human cells.
Prior art vaccines have often made use of purification of so called “blebs” which represent vesicles shed from the cell surface of the particular organism of interest. However, such a crude product carries many problems. For example, there is wide variation in the composition of these blebs. There is no reliable way of controlling which proteins are included or excluded from these blebs. These blebs may or may not include polysaccharide-coating elements of the organism of interest. The proportions of the various components of the blebs in relation to one another cannot be reliably determined. The composition of these blebs cannot be easily determined or controlled.
Many attempts have been made to develop vaccines based on the sub-capsular antigens, especially the outer membrane proteins (OMPs). Meningococcal OMPs are highly diverse and, although OMP-containing outer membrane vesicle (OMV) vaccines have been effective against the particular epidemic strain from which they were made, levels of potentially cross-protective immune responses to heterologous strains have been disappointing.
One prior art vaccine is the so called OMV (outer membrane vesicle) vaccine. This has included up to nine different PorA proteins. This nine fold vaccine is made up of OMVs produced from three different strains of bacterium, each bearing its naturally occurring PorA plus two further PorA's which have been engineered into each of the three strains. This is the so called “conventional” vaccine. As such, it suffers from similar problems are as present in other parts of the prior art such as are associated with vesicle vaccines generally. These problems include difficulty in controlling the levels of antigen present, the difficulties associated with the fact that this is a vesicle based vaccine and include the crude nature of the preparation used.
OMV vaccines containing outer membrane proteins (OMPs) have been used in the control of epidemics caused by single strains in Norway and Cuba. Due to the high antigenic diversity of many OMPs among different strains, immune responses to vaccines of this type are usually limited to the strains used in their manufacture or their close relatives. Consequently, this approach does not provide effective control of endemic serogroup B disease, which is attributed to diverse strains.
Feavers et al 1996 (Clinical and Diagnostic Laboratory Immunology Volume 3 pp 444-450) discusses the antigenic diversity of the meningococcal PorA outer membrane protein. A wide ranging serological and nucleic acid typing study is described. Medical problems presented by antigenic variability are discussed in relation to vaccine design. Although PorA protein vaccines are mentioned, they are mentioned in the context of illustrating the problems associated with the design of protein component vaccines directed against a variable antigen. Indeed, the unpredictability of these vaccines is discussed, and the efforts towards identification of conserved antigens are summarised.
Thompson et al 2003 (Microbiology Volume 149 pp. 1849-1858) reports extensively on the antigenic diversity of the meningococcal FetA protein. FetA is shown to be very highly diverse. Out of 107 individual N. meningitidis isolates examined, 60 different FetA alleles were identified. These 60 alleles encoded 56 different FetA protein sequences. Thompson et al explained that the diversity of this FetA protein will compromise its effectiveness as a vaccine component. Indeed, it is thought to be present in certain outer membrane vesicle (OMV) vaccines, but these vaccines suffer from the problem of strain specificity. Indeed, in order to expand the coverage of protection using OMV vaccines, OMVs derived from each invasive genotype predominant in a particular area would be needed to be included in vaccine formulations. The conclusions reached in Thompson et al are that FetA is so diverse it is likely to be largely ineffective in vaccine formulations and that conserved antigens probably offer the best way forward in vaccine development.
The present invention seeks to overcome problem(s) associated with the prior art.